Population Pharmacokinetic Analysis of the MDM2 Inhibitor KRT-232 (formerly AMG 232) in Subjects with Advanced Solid Tumors, Multiple Myeloma or Acute Myeloid Leukemia

Introduction

KRT-232 is a potent and selective, targeted small molecule inhibitor of human mouse double minute 2 (MDM2) homolog interactions with tumor protein 53 (p53). MDM2 prevents p53 activation and reduces p53-mediated transcription and cell cycle control. KRT-232 is under development by Kartos Therapeutics for treatment of myelofibrosis, polycythemia vera, acute myeloid leukemia (AML) and Merkel cell carcinoma (see NCT03662126, NCT03669965, NCT03787602).

Study 20120106 was a 2-part Phase 1 dose-exploration/dose-expansion study of KRT-232 in patients with advanced solid tumors or multiple myeloma (Gluck et al. Invest New Drugs in press; NCT01723020). Study 20120234 was a Phase 1b study evaluating KRT-232 alone and combined with trametinib, in patients with relapsed/refractory AML (Erba et al. Blood Adv 2019; NCT02016729).

This population PK analysis quantified the KRT-232 PK time-course and variability, and the contribution of subject covariates to PK variability, using data from Amgen studies 20120106 and 20120234.

Methods

Study 20120106: Subjects received KRT-232 doses of 15 mg (n=3), 30 mg (n=3), 60 mg (n=4), 120 mg (n=7), 240 mg (n=76), 300 mg (n=4), 360 mg (n=4) and 480 mg (n=6). Doses were administered once daily (QD) for 7 days in 21-day cycles. PK sampling occurred on Cycle 1 days 1 and 7, at nominal sampling times pre-dose and 1, 3, 5, 7, and 24 h post-dose, and 72 h after the day 7 dose.

Study 20120234: Subjects received KRT-232 doses of 60 mg (n=14; n=10 co-administered with 2 mg trametinib once daily, n=4 as single agent), 180 mg (n=5), 240 mg (n=3), and 360 mg (n=10). KRT-232 was administered QD for 7 days in 14-day cycles. PK sampling occurred on days 1 and 7, at nominal sampling times pre-dose and 1, 2, 4, 6, and 24 h post-dose, and 72 h after the day 7 dose.

Population PK modeling was conducted using the first-order conditional estimation (FOCE-I) method in NONMEM^® 7.3. Model covariates were selected using a forward addition and backward elimination method, based on significance levels of p<0.05 and p<0.01, respectively. Tested covariates included age, sex, weight, race, ethnicity, creatinine clearance, total bilirubin, AST, ALT, albumin, tumor type, disease stage, ECOG performance status, and the presence/absence of trametinib. Model quality was checked by inspection of model parameters and their confidence intervals, and standard residual-based and simulation-based diagnostics.

Results

KRT-232 plasma concentrations from 141 subjects with 1783 samples could be described by a two-compartment model with first-order absorption. Apparent oral clearance (CL/F) of KRT-232 was estimated to be 24.9 L/h (CV 61.5%) in subjects with solid tumors. The apparent oral central volume (Vc/F) and peripheral volume (Vp/F) were 62.9 L and 333 L, respectively. The terminal half-life was 17.1 hr.

The prediction-corrected visual predictive check in Figure A suggested that the median, 5th and 95th percentiles of the measured plasma KRT-232 concentrations aligned with modeled concentrations for 24 h post-dose; the modeled variability was larger than the measured variability at 72 h post-dose. Residual diagnostics confirmed an adequate model fit.

Apparent oral clearance did not change with dose over the studied dose range of 15-480 mg QD, indicating AUC increases were dose-proportional (Figure B).

Relative to solid tumor subjects, AML subjects had 61.6% greater steady-state AUC (Figure C). A subject with decreased albumin at the 5th percentile (30 g/L) was modeled to have a 47.7% increase in AUC and an 87.2% increase in C_min at steady state, relative to a typical subject with a median albumin level of 39 g/L. Trametinib and multiple myeloma model covariates had confidence intervals overlapping the line of unity. Covariates weight, sex, age, race and ethnicity did not affect CL/F or Vc/F. No effects of renal parameters, hepatic parameters, or ECOG performance status on CL/F were detected.

Conclusion

A two-compartment linear PK model with first-order absorption adequately described KRT-232 PK. Apparent oral clearance did not change with dose, indicating AUC increases were dose-proportional. AML subjects and subjects with decreased albumin had greater steady-state AUC values relative to subjects with solid tumors and normal albumin levels, although the magnitude of these effects were less than 2-fold.

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